Glucagon-like peptide-1 receptor is involved in learning and neuroprotection

被引:696
作者
During, MJ
Cao, L
Zuzga, DS
Francis, JS
Fitzsimons, HL
Jiao, XY
Bland, RJ
Klugmann, M
Banks, WA
Drucker, DJ
Haile, CN
机构
[1] Univ Auckland, Dept Mol Med & Pathol, Auckland 86716, New Zealand
[2] Thomas Jefferson Univ, Jefferson Med Coll, Dept Neurosurg, CNS Gene Therapy Ctr, Philadelphia, PA 19107 USA
[3] St Louis Univ, Sch Med, Dept Internal Med, Div Geriatr, St Louis, MO 63106 USA
[4] St Louis Univ, Sch Med, Vet Affiars Med Ctr St Louis, GRECC, St Louis, MO 63106 USA
[5] Univ Toronto, Toronto Gen Hosp, Dept Med, Banting & Best Diabet Ctr, Toronto, ON M5G 2C4, Canada
基金
美国国家卫生研究院;
关键词
D O I
10.1038/nm919
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Glucagon-like peptide-1 (GLP-1) is a gut peptide that, together with its receptor, GLP-1R, is expressed in the brain. Here we show that intracerebroventricular (i.c.v.) GLP-1 and [Ser(2)]exendin(1-9) (HSEGTFTSD; homologous to a conserved domain in the glucagon/GLP-1 family) enhance associative and spatial learning through GLP-1R. [Ser(2)]exendin(1-9), but not GLP-1, is also active when administered peripherally. GLP-1R-deficient mice have a phenotype characterized by a learning deficit that is restored after hippocampal Glp1r gene transfer. In addition, rats overexpressing GLP-1R in the hippocampus show improved learning and memory. GLP-1R-deficient mice also have enhanced seizure severity and neuronal injury after kainate administration, with an intermediate phenotype in heterozygotes and phenotypic correction after Glp1r gene transfer in hippocampal somatic cells. Systemic administration of [Ser(2)]exendin(1-9) in wild-type animals prevents kainate-induced apoptosis of hippocampal neurons. Brain GLP-1R represents a promising new target for both cognitive-enhancing and neuroprotective agents.
引用
收藏
页码:1173 / 1179
页数:7
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